Imidazole compounds as transforming growth factor (TGF) inhibitors

ABSTRACT

Novel imidazole compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use are described. The compounds of the present invention are potent inhibitors of transforming growth factor (“TGF”)-  signaling pathway. They are useful in the treatment of various TGF-related disease states including, for example, cancer and fibrotic diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 10/666,192 filed Sep. 17, 2003, now allowed, which claims benefit ofpriority from U.S. Provisional Patent Application No. 60/411,894 filedSep. 18, 2002, and U.S. Provisional Patent Application No. 60/484,522filed Jul. 2, 2003.

RELATED APPLICATIONS

This application claims benefit of priority under 35 U.S.C 119(e) toU.S. Provisional Application No. 60/411,894 filed on Sep. 18, 2002, and60/484,522 filed on Jul. 2, 2003, each of which is herein incorporatedin its entirety by reference.

BACKGROUND OF THE INVENTION

The present invention relates to novel imidazole compounds, includingderivatives thereof, to intermediates for their preparation, topharmaceutical compositions containing them and to their medicinal use.The compounds of the present invention are potent inhibitors of thetransforming growth factor (“TGF”)-

signaling pathway. They are useful in the treatment of TGF-β relateddisease states including, for example, cancer and fibrotic diseases.

TGF-β activates both antiproliferative and tumor-promoting signalingcascades. Three mammalian TGF-

isoforms have been identified (TGFβI, -βII, and -βIII). TGF-β productionpromotes tumor progression while its blockade enhances antitumoractivity. Blockade of TGF-β enhances antitumor immune responses andinhibits metastasis. Thus there exists a need in the art for compoundsthat inhibit the TGF-

signaling pathway. The present invention, as described below, answerssuch a need.

SUMMARY OF THE INVENTION

The present invention provides a novel compound containing a coreimidazole ring substituted with at least one substituted orunsubstituted 2-pyridyl moiety and at least one R¹ moiety as set forthherein, and all pharmaceutically acceptable salts, prodrugs, tautomers,hydrates, and solvates thereof. In a compound of the invention, thesubstituted or unsubstituted 2-pyridyl moiety and R¹ moiety can be in an1,2-, 1,3- or 1,4-relationship around the core imidazole ring;preferably, in an 1,2- or ortho relationship.

The present invention provides a compound of the formula (Ia):

and all pharmaceutically acceptable salts, prodrugs, tautomers,hydrates, and solvates thereof, where R¹, R³, R⁴, R⁶, and s are each asset forth below, with the proviso that when R⁴ is a substituted phenylgroup, then (a) R¹ is not a naphthyl, anthracenyl or phenyl and (b) ifR¹ is a phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7members wherein said cyclic ring optionally contains up to threeheteroatoms independently selected from N, O and S, then the fusedcyclic ring of said R¹ moiety is substituted; and

with the proviso that when R⁴ is hydrogen, then (a) R¹ is not a naphthylor phenyl and (b) if R¹ is a phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to three heteroatoms independently selected fromN, O and S, then the fused cyclic ring of said R¹ moiety is substituted;and

with the proviso that when R⁴ is not hydrogen or substituted phenyl,then (a) R¹ is not a naphthyl, anthracenyl or phenyl and (b) if R¹ is aphenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of5-7 members wherein said cyclic ring optionally contains up to threeheteroatoms independently selected from N, O and S, and is optionallysubstituted by oxo (═O), then the fused cyclic ring of said R¹ moietycontains at least one substituted heteroatom.

In formula (Ia), as set forth above:

R¹ is a saturated, unsaturated, or aromatic C₃-C₂₀ mono-, bi- orpolycyclic ring optionally containing at least one heteroatom selectedfrom the group consisting of N, O and S, wherein R¹ can optionally befurther independently substituted with at least one moiety independentlyselected from the group consisting of: carbonyl, halo, halo(C₁-C₆)alkyl,perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy, oxo, mercapto, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy,(C₅-C₁₀)aryl or (C₅-C₁₀)heteroaryl, (C₅-C₁₀)aryloxy or(C₅-C₁₀)heteroaryloxy, (C₅-C₁₀)ar(C₁-C₆)alkyl or(C₅-C₁₀)heteroar(C₁-C₆)alkyl, (C₅-C₁₀)ar(C₁-C₆)alkoxy or(C₅-C₁₀)heteroar(C₁-C₆)alkoxy, HO—(C═O)—, ester, amido, ether, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl,(C₁-C₆)alkyl- and di(C₁-C₆)alkylamino, cyano, nitro, carbamoyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylaminocarbonyl,di(C₁-C₆)alkylaminocarbonyl, (C₅-C₁₀)arylcarbonyl,(C₅-C₁₀)aryloxycarbonyl, (C₁-C₆)alkylsulfonyl, and (C₅-C₁₀)arylsulfonyl;

preferably, R¹ can optionally be further independently substituted withzero to two moieties independently selected from the group consistingof, but not limited to, halo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl,perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₅-C₁₀)ar(C₁-C₆)alkoxy or (C₅-C₁₀)heteroar(C₁-C₆)alkoxy, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl;

each R³ is independently selected from the group consisting of:hydrogen, halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₅-C₁₀)heteroaryl-O—,(C₅-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, O₂N—, NC—, amino,Ph(CH₂)₁₋₆HN—, (C₁-C₆)alkyl HN—, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, amino(C═O)—, aminoO₂S—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—; preferably, R³ is hydrogen or (C₁-C₆)alkyl; morepreferably, R³ is hydrogen or methyl;

where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic,cycloalkyl, alkoxy, phenoxy, amino of R³ is optionally substituted by atleast one substituent independently selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂N—, Ph(CH₂)₁₄HN—, and(C₁-C₆)alkylHN—;

s is an integer from one to five; preferably, one to two; morepreferably, one;

R⁴ is independently selected from the group consisting of: hydrogen,halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₅-C₁₀)heteroaryl-O—, (C₅-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-S—(C₁-C₆)alkyl-,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, O₂N—, NC—, amino, aminoalkyl,Ph(CH₂)₁₋₆HN—, (C₁-C₆)alkylHN—, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂-NH—, amino(C═O)—, aminoO₂S—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—((C₁-C₆)alkyl)-N—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, ((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl,(C₁-C₆)alkyl-NH—(C═O)—(C₁-C₆)alkyl, and (C₁-C₆)alkyl-(C═O)—(C₁-C₆)alkyl;preferably, R⁴ is hydrogen, (C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, phenyl,(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-, (C₅-C₁₀)heteroaryl, (C₃-C₁₀)cycloalkyl,aminoalkyl, amino(C═O)—, (C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl, or(C₁-C₆)alkyl-NH—(C═O)—(C₁-C₆)alkyl; more preferably, R⁴ is hydrogen,methyl, t-butyl, trifluoromethyl, phenol, isopropyl, thiazole,cyclopropyl, or H₂NC(═O)— or methanol;

where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic,cycloalkyl, alkoxy, phenoxy, amino of R⁴ is optionally substituted by atleast one substituent independently selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂N—, NC—, HO—,Ph (CH₂)₁₋₆HN—, (C₁-C₆)alkylHN—, (C₅-C₁₀)heteroaryl and(C₅-C₁₀)heterocyclyl; preferably, halo, HO—, NC—, (C₅-C₁₀)heteroaryl;

R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-(SO₂)—,(C₁-C₆)alkyl-(SO₂)—(C₁-C₆)alkyl, phenyl-(SO₂)—, H₂N—(SO₂)—,(C₁-C₆)alkyl-NH—(SO₂)—, (C₁-C₆)alkyl-(SO₂)—NH—(C₁-C₆)alkyl,(C₁-C₆)alkyl-NH—(SO₂)—(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂N—(SO₂)—,phenyl-NH—(SO₂)—, (phenyl)₂N—(SO₂)—, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-(C═O)—(C₁-C₆)alkyl, phenyl-(C═O)—,(C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—(C₃-C₁₀)cycloalkyl,(C₁-C₆)alkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl,phenyl-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—(C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyl-(C═O)—NH—(C₃-C₁₀)cycloalkyl, ((C₁-C₆)alkyl)₂N—(C═O)—,(phenyl)₂N—(C═O)—, phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heteroaryl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heterocyclic-[((C₁-C₆)alkyl)-N]—(C═O)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)-N]—(C═O)—; preferably, R⁶ is H,(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-(SO₂)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(SO₂)—NH—(C₁-C₆)alkyl, (C₁-C₆)alkyl-NH—(SO₂)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl-(C═O)—(C₃-C₁₀)cycloalkyl,(C₁-C₆)alkyl-NH—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl-NH—(C═O)—(C₃-C₁₀)cycloalkyl, or(C₃-C₁₀)cycloalkyl-(C═O)—NH—(C₃-C₁₀)cycloalkyl;

where alkyl, alkenyl, alkynyl, phenyl, benzyl, heteroaryl, heterocyclic,cycloalkyl, alkoxy, phenoxy, amino of R⁶ is optionally substituted withat least one moiety independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₅-C₁₀)heterocyclic,(C₅-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, NC—, (C₁-C₆)alkyl-(C═O)—,(C₃C₁₀)cycloalkyl-(C=O)—, phenyl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₅-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₅-C₁₀)beteroaryl-NH—(C═O)—,((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₅-C₁₀)heterocyclic-O—, (C₅-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₅-C₁₀)heterocyclic-(C═O)—O—, (C₅-C₁₀)heteroaryl-(C═O)—O—, O₂N—, amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₅-C₁₀)heterocyclic-(C═O)—NH—, (C₅-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-(C═O)—[(C₁-C₆)alkyl-N]—,(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—,(C₅-C₁₀)heterocyclic-SO₂NH— and (C₅-C₁₀)heteroaryl-SO₂NH—; preferably,R⁶ is substituted with zero to two groups independently selected fromthe group consisting of (C₁-C₆)alkyl and (C₃-C₁₀)cycloalkyl;

wherein the phenyl or heteroaryl moiety of a R⁶ substituent isoptionally further substituted with at least one radical independentlyselected from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,perfluoro(C₁-C₆)alkyl and perfluoro(C₁-C₆)alkoxy,

with the proviso that when R⁴ is a substituted phenyl group, then (a) R¹is not a naphthyl, anthracenyl or phenyl and (b) if R¹ is a phenyl fusedwith an aromatic or non-aromatic cyclic ring of 5-7 members wherein saidcyclic ring optionally contains up to three heteroatoms independentlyselected from N, O and S, then the fused cyclic ring of said R¹ moietyis substituted; and

with the proviso that when R⁴ is hydrogen, then (a) R¹ is not a naphthylor phenyl and (b) if R¹ is a phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to three heteroatoms independently selected fromN, O and S, then the fused cyclic ring of said R¹ moiety is substituted;and

with the proviso that when R⁴ is not hydrogen or substituted phenyl,then (a) R¹ is not a naphthyl, anthracenyl or phenyl and (b) if R¹ is aphenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of5-7 members wherein said cyclic ring optionally contains up to threeheteroatoms independently selected from N, O and S, and is optionallysubstituted by oxo, then the fused cyclic ring of said R¹ moietycontains at least one substituted heteroatom.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

Each of R¹ above can optionally be further substituted by at least oneR^(2a) group, as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein and where the proviso language doesnot apply.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is selected from the group consisting of:

and where the proviso language does not apply.

In another embodiment of the invention, R¹ of formula of (Ia), as setforth above, is selected from the group consisting of:

and where the proviso language does not apply.

In another embodiment of the invention, R¹ of formula of (Ia), as setforth above, is selected from the group consisting of:

where R^(2a) is as set forth herein and where the proviso language doesnot apply.

The invention also provides a pharmaceutical composition comprising atleast one compound of the invention and a pharmaceutically acceptablecarrier.

The invention further provides a method of preparation of a compound ofthe invention.

The invention still further provides a method of preventing or treatinga TGF-related disease state in an animal or human comprising the step ofadministering a therapeutically effective amount of at least onecompound of the invention to the animal or human suffering from theTGF-related disease state.

The invention still further provided the use of a compound in thepreparation of a medicament for the prevention or treatment of aTGF-related disease state in an animal or human.

DEFINITIONS

As used herein, the article “a” or “an” refers to both the singular andplural form of the object to which it refers.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy) refers to a linear or branchedsaturated hydrocarbon (e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, secondary-butyl, tertiary-butyl).

As used herein, the term “cycloalkyl” refers to a mono or bicycliccarbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl).

As used herein, the term “halogen” or “halo” refers to includes fluoro,chloro, bromo or iodo or fluoride, chloride, bromide or iodide.

As used herein, the term “halo-substituted alkyl” or “haloalkyl” refersto an alkyl radical, as set forth above, substituted with one or morehalogens, as set forth above, including, but not limited to,chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, and 2,2,2-trichloroethyl.

As used herein, the term “perhaloalkyl” refers to an alkyl radical, asset forth above, where each hyrdrogen of the alkyl group is replacedwith a “halogen” or “halo”, as set forth above.

As used herein, the term “alkenyl” refers to a linear or branchedhydrocarbon chain radical containing at least two carbon atoms and atleast one double bond. Examples include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

As used herein, the term “alkynyl” refers to a linear or branchedhydrocarbon chain radical having at least one triple bond including, butnot limited to, ethynyl, propynyl, and butynyl.

As used herein, the term “carbonyl” refers to a >C═O moiety.Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refers to an alkyl carbamategroup. The carbonyl group is also equivalently defined herein as (C═O).

As used herein, the term “phenyl-[(alkyl)-N]—(C═O)—” refers to aN,N′-disubstituted amide group of the formula

As used herein, the term “aryl” refers to an aromatic radical such as,for example, phenyl, naphthyl, tetrahydronaphthyl, and indanyl.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining at least one heteroatom selected from O, S and N. Forexample, heteroaryl groups include, but are not limited to, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl,pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g.,1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, and indolyl.

As used herein, the term “heterocyclic” refers to a saturated orunsaturated C₃-C₂₀ mono-, bi- or polycyclic group containing at leastone heteroatom selected from N, O, and S. Examples of heterocyclicgroups include, but are not limited to, azetidinyl, tetrahydrofuranyl,imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl,thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl,oxazinyl, oxcithiazinyl, indolinyl, isoindolinyl, quincuclidinyl,chromanyl, isochromanyl, benzocazinyl, and the like. Examples ofmonocyclic saturated or unsaturated ring systems aretetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl,isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,and 1,2,5-oxathiazin-4-yl.

As used herein, the term “pharmaceutically acceptable acid additionsalt” refers to non-toxic acid addition salts, i.e., salts derived frompharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

As used herein, the term “pharmaceutically acceptable base additionsalt” refers to non-toxic base addition salts, i.e., salts derived fromsuch pharmacologically acceptable cations such as alkali metal cations(e.g. potassium and sodium) and alkaline earth metal cations (e.g.,calcium and magnesium), ammonium or water-soluble amine addition saltssuch as N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines.

As used herein, the term “suitable substituent”, “substituent”, or“substituted” refers to a chemically and pharmaceutically acceptablefunctional group, i.e., a moiety that does not negate the inhibitoryand/or therapeutic activity of the inventive compounds. Such suitablesubstituents may be routinely selected by those skilled in the art.Illustrative examples of suitable substituents include, but are notlimited to, carbonyl, halo, haloalkyl, perfluoroalkyl, perfluoroalkoxy,alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, arylor heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl,aralkoxy or heteroaralkoxy, HO—(C═O)—, ester, amido, ether, amino,alkyl- and dialkylamino, cyano, nitro, carbamoyl, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl,aryloxycarbonyl, alkylsulfonyl, arylsulfonyl and the like. Those skilledin the art will appreciate that many substituents can be substituted byadditional substituents.

As used herein, the term “TGF-related disease state” refers to anydisease state mediated by the production of TGF-β.

As used herein, the term “Ph” refers to phenyl.

As used herein, the term “a saturated, unsaturated, or aromatic C₃-C₂₀mono-, bi- or polycyclic ring optionally containing at least oneheteroatom” refers to, but is not limited to,

where R^(2a) is independently selected from the group consisting of:(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₁₀)cycloalkyl,(C₅-C₁₀)aryl, (C₁-C₆)alkylaryl, amino, carbonyl, carboxyl, (C₂-C₆)acid,(C₁-C₆)ester, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclyl, (C₁-C₆)alkoxy,nitro, halo, hydroxyl, (C₁-C₆)alkoxy(C₁-C₆)ester, and those groupsdescribed in U.S. application Ser. Nos. 10/094,717, 10/094,760, and10/115,952, each of which is herein incorporated in its entirety byreference; and where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, amino,acid, ester, heteroaryl, heterocyclyl, and alkoxy of R^(2a) isoptionally substituted by at least one moiety independently selectedfrom the group consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₃-C₁₀)cycloalkyl,(C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, formyl, NC—,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, ((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, O₂N—, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂-amino, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, H₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—NH—, ((C₁-C₆)alkyl)₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—[((C₁-C₆)alkyl)-N]—,((C₁-C₆)alkyl)₂N—(C═O)—[(C₁-C₆)alkyl-N]—, phenyl-HN—(C═O)—NH—,(phenyl)₂N—(C═O)—NH—, phenyl-HN—(C═O)—[((C₁-C₆)alkyl)-N]—,(phenyl-)₂N—(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₁-C₆)alkyl-O—(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-O—(C═O)—NH—,phenyl-O—(C═O)-[(alkyl)-N]—, (C₁-C₆)alkyl-SO₂NH—, phenyl-SO₂NH—,(C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)ester-(C₁-C₆)alkyl-O—, phenyl-(C═O)—O—, H₂N—(C═O)—O—,(C₁-C₆)alkyl-HN—(C═O)—O—, ((C₁-C₆)alkyl)₂N—(C═O)—O—, phenyl-HN—(C═O)—O—,and (phenyl)₂N—(C═O)—O—.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction schemes illustrate the preparation of thecompounds of the present invention. A compound of the invention may beprepared by methods analogous to those described in U.S. applicationSer. Nos. 10/094,717, 10/094,760, and 10/115,952 and WO 02/40476. Unlessotherwise indicated, R¹, R³, R⁴, R⁶, and s in the reaction schemes andthe discussion that follow are defined above.

Scheme 1 refers to the preparation of compounds of the formula (Ia)where R⁶═H. Referring to Scheme 1, a compound of the formula IV wasprepared from a compound of the formula II by treating with a base, suchas butyl lithium, at a temperature of about −60° C. for a time period ofabout 90 minutes, followed by the slow addition of an amide of theformula III, which is either commercially available or preparedaccording to Preparation B, as set forth below, in a polar aproticsolvent, such as tetrahydrofuran. The aforesaid reaction was run at atemperature from about −78° C. to about 0° C., preferably about −20° C.,for a period from about 1 hour to about 10 hours, preferably about 3hours.

Alternatively the compound of formula IV is prepared according to themethods of Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.;Cai, D.-W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.;DiMichele, L.; Dormer, P.; Reider, P. J.; J. Org. Chem., Vol. 65, pp.8415-8420 (2000).

The compound of formula V is prepared from a compound of the formula IVby reaction with an oxidizing reagent in a polar protic solvent.Suitable oxidizing reagents include hydrogen bromide, cuprous acetate,pyridiniumchlorochromate (PCC) and tetrapropylammoniumperuthenate/N-methyl morpholine-N-oxide (TPAP/NMO), preferably cuprousacetate. Suitable solvents include acetic acid and dimethyl sulfoxide.The aforesaid reaction can be run neat or in the presence of a solventsuch as alcohols (e.g., methanol, ethanol or butanol) and acetic acid.The aforesaid reaction can be run at a temperature from about 20° C. toabout 80° C. for a period from about 15 minutes to about 4 hours.Preferably, the reaction is run under neat conditions at about 60° C.for about 3 hours.

A compound of the formula (Ia) can be prepared from a compound offormula V by reaction with R⁴—(C═O)H in the presence of an ammoniasource. Suitable ammonia sources include ammonium trifluoroacetate,ammonia, and ammonium acetate, preferably ammonium acetate. Theaforesaid reaction can be run neat or in the presence of a solvent suchas alcohols (e.g., methanol, ethanol or butanol) and acetic acid. Theaforesaid reaction can be run at a temperature from about 20° C. toabout 80° C. for a period from about 15 minutes to about 4 hours,preferably neat conditions at about 60° C. for about 2 hours.

Alternatively, compound of the formula (Ia) can be prepared according tothe procedures set forth in WO 02/72576.

Scheme 2 refers to the preparation of compounds of the formula IV, whichare intermediates useful in the preparation of compounds of the formula(Ia). Referring to Scheme 2, compounds of the formula VII were preparedfrom aldehydes of the formula VI by first treatment with an aromaticamine, such as aniline, in a polar solvent. Suitable solvents includeethyl acetate, isopropyl acetate, or tetrahydrofuran, preferablyisopropyl acetate. The resulting reaction mixture is heated to atemperature from about 50° C. to about 100° C., preferably about 60° C.,and then slowly treated with phosphorous acid diphenyl ester. Thetemperature of the reaction mixture was maintained for a period fromabout 30 minutes to about 3 hours, preferably about 1 hour, and thencooled to ambient temperature overnight.

A compound of the formula IV was prepared from a compound of the formulaVII by reaction with a pyridine aldehyde of the formula VIII in thepresence of a base, such as potassium tert-butoxide, in a polar solvent.Suitable solvents for the aforesaid reaction include ethyl acetate,isopropyl acetate, or tetrahydrofuran, preferably a mixture oftetrahydrofuran and isopropyl acetate. The aforesaid reaction was run ata temperature from about 0° C. to about 100° C., preferably about 22° C.(ambient temperature), for a period from about 30 minutes to about 5hours, preferably about 2 hours. The resulting reaction mixture was thentreated with acid, such as hydrochloric acid for a period from about 30minutes to about 5 hours, preferably about 1 hour.

The compound of formula VI can be prepared according to Preparation A,set forth below. The compound of formula VI can also be preparedaccording to the methods of Davies, I. W.; Marcoux, J.-F.; Corley, E.G.; Journet, M.; Cai, D.-W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen,K.; Pye, P. J.; DiMichele, L.; Dormer, P.; Reider, P. J.; J. Org. Chem.,Vol. 65, pp. 8415-8420 (2000).

A compound of the formula VIII was prepared according to Preparation Dset forth below.

Scheme 3 refers to the preparation of compounds of the formula XI, whichare intermediates useful in the preparation of compounds of the formula(Ia). Referring to Scheme 3, compounds of the formula IX were preparedfrom pyridine aldehydes of the formula VIII in a manner analogous to theprocedure described in Scheme 2 for the preparation of a compound of theformula VII from a compound of the formula VI. A compound of formulaVIII can be prepared according to Preparation D set forth below.

A compound of the formula XI was prepared by reaction of a compound ofthe formula IX with a compound of the formula X under conditionsanalogous to those described in Scheme 2 for the preparation of acompound of the formula IV from a compound of the formula VII.

Alternatively the compound of formula XI can be prepared according tothe methods of Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet,M.; Cai, D.-W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P.J.; DiMichele, L.; Dormer, P.; Reider, P. J.; J. Org. Chem., Vol. 65,pp. 8415-8420 (2000).

A compound of formula XI can be converted to a compound of formula (Ia)by methods analogous to those described in Scheme 1 for the conversionof compound IV to compound V to compound of formula (Ia).

Scheme 4 refers to the preparation of compounds of the formula Ia whereR¹ is

Referring to Scheme 4, compounds of the formula XIII were prepared fromcompounds of the formula XII, which are either commercially available orcan be prepared according to the procedure described in Preparation Afor the preparation of compound XVI or in Preparation C, each as setforth below. In Scheme 4 the compounds (Ia) were be prepared fromcompound XIII according to procedures described in Scheme 1.

Scheme 5 refers to the preparation of a compound of formula (Ia) whereR⁶ is other than H. Referring to Scheme 5, such a compound was preparedby reaction of a compound of formula (Ia) where R⁶ is H with analkylating reagent of the formula R⁶L′, wherein L′ is halo or otherleaving group such as mesyl, in the presence of a base and a solvent.Suitable bases include sodium hydride and cesium carbonate. Suitablesolvents include dimethyl sulfoxide, NN-dimethylformamide. The aforesaidreaction is conducted at a temperature from about 0° C. to about 30° C.,preferably about 22° C., for a period from about 10 minutes to about 2hours, preferably about 1 hour. A compound of formula (Ia) where R⁶ is Hwas prepared according to Scheme 1, set forth above.

PREPARATION A

Preparation A refers to the preparation of compounds of the formula VI,which are intermediates useful in the preparation of compounds of theformula VIII and XI in Scheme 2 and Scheme 3, respectively. InPreparation A, R is a simple alkyl group such as methyl or ethyl.Referring to Preparation A, compounds of the formula XVI were preparedfrom a compound of the formula XV, wherein X is a chloride or bromide,by an alkoxycarbonylation reaction. Suitable conditions includemetal-halogen exchange with butyl lithium in a solvent such astetrahydrofuran at a temperature of about 0° C, for a period of time ofabout 30 minutes, followed by the addition of ethylchloroformate at atemperature of about 0° C., followed by a period of time of about 2.4hours at about 50° C.

The compound of the formula VI was prepared from a compound of theformula XVI by a two-step process. First the compound of formula XVI wastreated with a reducing agent in a suitable solvent. Suitable reducingagents include lithium borohydride, sodium borohydride, lithium aluminumhydride, and borane in tetrahydrofuran. Suitable solvents includemethanol, ethanol, tetrahydrofuran, diethyl ether, and dioxane. Theaforesaid reaction was run at a temperature from about 0° C. to about100° C., preferably about 65° C., for a period from about 10 minutes toabout 1 hour, preferably about 30 minutes. The resulting primary alcoholwas then oxidized to the corresponding aldehyde of the formula VI bytreatment with an oxidizing agent, such as N-methyl morpholineN-oxide/TPAP, Dess-Martin reagent, PCC or oxalyl chloride-DMSO,preferably oxalyl chloride-DMSO in a suitable solvent. Suitable solventsfor the aforesaid reaction include chloroform, tetrahydrofuran, ordichloromethane. The aforesaid reaction was conducted at a temperaturefrom about −78° C. to about 22° C. for a time from about 15 minutes toabout 3 hours, preferably about 1 hour.

PREPARATION B

Preparation B refers to the preparation of compounds of the formula III,which are intermediates useful in the preparation of compounds of theformula (Ia). In Preparation B, R is a simple alkyl group such as methylor ethyl. Referring to Preparation B, compounds of the formula XVIIIwere prepared from a compound of the formula XVII, which may be preparedaccording to a procedure described in Preparation A or are commerciallyavailable, by treatment with a base such as lithium hydroxide, in apolar protic solvent. Suitable solvents for the aforesaid reactionincluded methanol, ethanol, and water. The aforesaid reaction wasconducted at a temperature from about 0° C. to about 30° C., preferablyabout 22° C. (room temperature) for a time from about 15 minutes toabout 3 hours, preferably about 1 hour.

The compound of the formula III was prepared from a compound of theformula XVIII by reaction with a suitable activating agent and acompound of the formula

and a base. Suitable activating agents included thionyl chloride,carbonyldiimidazole, EDCI and DCC, preferably oxalyl chloride. Suitablebases included triethylamine, Hunig's base, or DBU, preferablytriethylamine. Suitable solvents for the aforesaid reaction includemethylene chloride, N,N′-dimethylformamide, tetrahydrofuran, and amixture thereof, preferably methylene chloride. The aforesaid reactionwas conducted at a temperature from about 0° C. to about 30° C.,preferably about 22° C. (room temperature) for a time from about 6 hoursto about 48 hours, preferably about 12 hours.

PREPARATION C

Preparation C refers to the preparation of compounds of the formula XII,which is an intermediate useful in the preparation of compounds offormula (Ia), as set forth above, where R¹ is

In Preparation C, R is (C₁-C₆)alkyl. The compound of formula XII wasprepared from a compound of formula XIX by treatment with an alkylhalide, such as methyl iodide, in the presence of a base such as sodiumhydride, in a polar aprotic solvent such as N,N′-dimethylfornamide.Compounds of the formula XIX are commercially available.

PREPARATION D

Preparation D refers to the preparation of compounds of the formulaVIII, which are intermediates useful in the preparation of compounds offormula (Ia), as set forth above. In Preparation D, R is a simple alkylgroup such as methyl or ethyl. Referring to Preparation D, compounds ofthe formula XXI were prepared from heteroarylhalides of the formula XX,wherein X is a chloride or bromide, under conditions analogous for thepreparation of compound XVI from compound XV described in Preparation Aset forth above.

The compound of the formula VIII was prepared from a compound of theformula XXI under conditions analogous to the two-step process describedfor the preparation of compound VI from compound XVI in Preparation Aset forth above.

PREPARATION E

Preparation E refers to the preparation of compounds of the formula XXVwhich are intermediates in the preparation of compounds of the formula(Ia). Referring to preparation E, compounds of formula XXV were preparedfrom compounds of formula XIV by a formylation reaction. Suitableconditions for formylation include metal halogen exchange withisopropylmagnesium chloride in a solvent such as tetrahydrofuran at atemperature of about 0° C., for a period of time of about 30 minutes,followed by the addition of N,N-dimethylformamide at a temperature ofabout 0° C., followed by a period of time of about 2.5 hours at atemperature of about 50° C.

Compounds of formula XXIII were prepared as described in the literature(Moran, D. B.; Morton, G. O.; Albright, J. D., J. Heterocycl. Chem.,Vol. 23, pp. 1071-1077 (1986)) or from compounds of formula XXII whereinL and L′, which can be the same or different, are chloride, bromide oriodide, by reaction with hydrazine. A compound of formula XIV wasprepared from a compound of formula XXIII by condensation of compoundXIV with a cyclization reagent such as acid chloride, acid anhydride,trialkylorthoacetate or trialkylorthoformate. Compounds of formula XXIIare commercially available.

All pharmaceutically acceptable salts, prodrugs, tautomers, hydrates andsolvates of a compound of the invention is also encompassed by theinvention.

A compound of the invention which is basic in nature is capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals and humans, it is often desirable inpractice to initially isolate a compound of the invention from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent, and subsequently convert the free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent such as, for example, methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is obtained.

The acids which can be used to prepare the pharmaceutically acceptableacid addition salts of the base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as chloride, bromide, iodide,nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,lactate, citrate or acid citrate, tartrate or bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate andpamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

A compound of the invention which is also acidic in nature, e.g.,contains a COOH or tetrazole moiety, is capable of forming base saltswith various pharmacologically acceptable cations. Although such saltsmust be pharmaceutically acceptable for administration to animals andhumans, it is often desirable in practice to initially isolate acompound of the invention from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free acid compound by treatment with an acidic reagent, andsubsequently convert the free acid to a pharmaceutically acceptable baseaddition salt. Examples of such pharmaceutically acceptable baseaddition salts include the alkali metal or alkaline-earth metal saltsand particularly, the sodium and potassium salts. These salts can beprepared by conventional techniques. The chemical bases which can beused as reagents to prepare the pharmaceutically acceptable baseaddition salts of this invention are those which form non-toxic basesalts with the herein described acidic compounds of the invention. Thesenon-toxic base salts include salts derived from such pharmacologicallyacceptable cations as sodium, potassium, calcium and magnesium, etc.These salts can easily be prepared by treating the corresponding acidiccompounds with an aqueous solution containing the desiredpharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternatively,they may also be prepared by mixing lower alkanolic solutions of theacidic compounds and the desired alkali metal alkoxide together, andthen evaporating the resulting solution to dryness in the same manner asbefore. In either case, stoichiometric quantities of reagents arepreferably employed in order to ensure completeness of reaction andmaximum product yields.

Isotopically-labeled compounds are also encompassed by the presentinvention. As used herein, an “isotopically-labeled compound” refers toa compound of the invention including pharmaceutical salts, prodrugsthereof, each as described herein, in which one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

By isotopically-labeling a compound of the present invention, thecompounds may be useful in drug and/or substrate tissue distributionassays. Tritiated (³H) and carbon-14 (¹⁴C) labeled compounds areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium (²H) canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the invention, includingpharmaceutical salts, prodrugs thereof, can be prepared by any meansknown in the art.

Stereoisomers (e.g., cis and trans isomers) and all optical isomers of acompound of the invention (e.g., R and S enantiomers), as well asracemic, diastereomeric and other mixtures of such isomers arecontemplated by the present invention.

The compounds, salts, prodrugs, hydrates, and solvates of the presentinvention can exist in several tautomeric forms, including the enol andimine form, and the keto and enamine form and geometric isomers andmixtures thereof. All such tautomeric forms are included within thescope of the present invention. Tautomers exist as mixtures of atautomeric set in solution. In solid form, usually one tautomerpredominates. Even though one tautomer may be described, the presentinvention includes all tautomers of the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of the invention that can beseparated into rotationally restricted isomers.

A compound of the invention, as described above, can be used in themanufacture of a medicament for the prophylactic or therapeutictreatment of a TGF-related disease state in an animal or human.

A compound of the invention is a potent inhibitor of transforming growthfactor (“TGF”)-β signaling pathway and are therefore of use in therapy.Accordingly, the present invention provides a method of preventing ortreating a TGF-related disease in an animal or human comprising the stepof administering a therapeutically effective amount of at least onecompound of the invention to the animal or human suffering from theTGF-related disease state.

As used herein, the term “therapeutically effective amount” refers to anamount of a compound of the invention required to inhibit the TGF-βsignaling pathway. As would be understood by one of skill in the art, a“therapeutically effective amount” will vary from patient to patient andwill be determined on a case by case basis. Factors to consider include,but are not limited to, the patient being treated, weight, health,compound administered, etc.

There are numerous disease states that can be treated by inhibition ofthe TGF-β signaling pathway. Such disease states include, but are notlimited to, all types of cancer (e.g., breast, lung, colon, prostate,ovarian, pancreatic, melanoma, all hematological malignancies, etc.) aswell as all types of fibrotic diseases (e.g., glomerulonephritis,diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis, arterialhyperplasia and restenosis, scleroderma, and dermal scarring).

The present invention also provides a pharmaceutical compositioncomprising at least one compound of the invention and at least onepharmaceutically acceptable carrier. The pharmaceutically acceptablecarrier may be any such carrier known in the art including thosedescribed in, for example, Remington's Pharmaceutical Sciences, MackPublishing Co., (A. R. Gennaro edit. 1985). A pharmaceutical compositionof the invention may be prepared by conventional means known in the artincluding, for example, mixing at least one compound of the inventionwith a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention may be used in theprevention or treatment of a TGF-related disease state, as describedabove, in an animal or human. Thus, a compound of the invention may beformulated as a pharmaceutical composition for oral, buccal, intranasal,parenteral (e.g., intravenous, intramuscular or subcutaneous), topical,or rectal administration or in a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical composition may take theform of, for example, a tablet or capsule prepared by conventional meanswith a pharmaceutically acceptable excipient such as a binding agent(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); filler (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricant (e.g., magnesium stearate,talc or silica); disintegrant (e.g., potato starch or sodium starchglycolate); or wetting agent (e.g., sodium lauryl sulphate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of a, for example, solution, syrupor suspension, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means with apharmaceutically acceptable additive such as a suspending agent (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g.,almond oil, oily esters or ethyl alcohol); and preservative (e.g.,methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

A compound of the present invention may also be formulated for sustaineddelivery according to methods well known to those of ordinary skill inthe art. Examples of such formulations can be found in U.S. Pat. Nos.3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397, which areherein incorporated by reference in their entirety.

A compound of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain a formulating agent such as a suspending,stabilizing and/or dispersing agent. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

A compound of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, acompound of the invention may be conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the compound of theinvention. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of a compound of the invention for oral, parenteral orbuccal administration to the average adult human for the treatment of aTGF-related disease state is about 0.1 mg to about 2000 mg, preferably,about 0.1 mg to about 200 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains about 20 μg to about 10,000 μg,preferably, about 20 μg to about 1000 μg of a compound of the invention.The overall daily dose with an aerosol will be within the range fromabout 100 μg to about 100 mg, preferably, about 100 μg to about 10 mg.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 mgto about 1000 mg, preferably, about 0.01 mg to about 100 mg of acompound of this invention, more preferably from about 1 mg to about 10mg of such compound. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses eachtime.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains from about 0.01 mg to about 20,000mg, preferably, about 0.01 mg to about 2000 mg of a compound of theinvention, more preferably from about 1 mg to about 200 mg.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

For topical administration, a compound of the invention may beformulated as an ointment or cream.

This invention also encompasses pharmaceutical compositions containingand methods of treatment or prevention comprising administering prodrugsof at least one compound of the invention. As used herein, the term“prodrug” refers to a pharmacologically inactive derivative of a parentdrug molecule that requires biotransformation, either spontaneous orenzymatic, within the organism to release the active drug. Prodrugs arevariations or derivatives of the compounds of this invention which havegroups cleavable under metabolic conditions. Prodrugs become thecompounds of the invention which are pharmaceutically active in vivo,when they undergo solvolysis under physiological conditions or undergoenzymatic degradation. Prodrug compounds of this invention may be calledsingle, double, triple etc., depending on the number ofbiotransformation steps required to release the active drug within theorganism, and indicating the number of functionalities present in aprecursor-type form. Prodrug forms often offer advantages of solubility,tissue compatibility, or delayed release in the mammalian organism (see,Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp.352-401, Academic Press, San Diego, Calif., 1992). Prodrugs commonlyknown in the art include acid derivatives well known to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacids with a suitable alcohol, or amides prepared by reaction of theparent acid compound with an amine, or basic groups reacted to form anacylated base derivative. Moreover, the prodrug derivatives of thisinvention may be combined with other features herein taught to enhancebioavailability. For example, a compound of the invention having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of the invention.The amino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof a compound of the invention through the carbonyl carbon prodrugsidechain.

According to the invention, in the treatment of a TGF-related diseasestate, a compound of the invention, as described herein, whether aloneor as part of a pharmaceutical composition may be combined with anothercompound(s) of the invention and/or with another therapeutic agent(s).Examples of suitable therapeutic agent(s) include, but are not limitedto, standard non-steroidal anti-inflammatory agents (hereinafterNSAID's) (e.g., piroxicam, diclofenac), propionic acids (e.g., naproxen,flubiprofen, fenoprofen, ketoprofen and ibuprofen), fenamates (e.g.,mefenamic acid, indomethacin, sulindac, apazone), pyrazolones (e.g.,phenylbutazone), salicylates (e.g., aspirin), COX-2 inhibitors (e.g.,celecoxib, valdecoxib, rofecoxib and etoricoxib), analgesics andintraarticular therapies (e.g., corticosteroids) and hyaluronic acids(e.g., hyalgan and synvisc), anticancer agents (e.g., endostatin andangiostatin), cytotoxic drugs (e.g., adriamycin, daunomycin,cis-platinum, etoposide, taxol, taxotere), alkaloids (e.g.,vincristine), and antimetabolites (e.g., methotrexate), cardiovascularagents (e.g., calcium channel blockers), lipid lowering agents (e.g.,statins), fibrates, beta-blockers, Ace inhibitors, Angiotensin-2receptor antagonists and platelet aggregation inhibitors, CNS agents(e.g., as antidepressants (such as sertraline)), anti-Parkinsonian drugs(e.g., deprenyl, L-dopa, Requip, Mirapex), MAOB inhibitors (e.g.,selegine and rasagiline), comP inhibitors (e.g., Tasmar), A-2inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotineagonists, Dopamine agonists and inhibitors of neuronal nitric oxidesynthase), anti-Alzheimer's drugs (e.g., donepezil, tacrine, COX-2inhibitors, propentofylline or metryfonate), osteoporosis agents (e.g.,roloxifene, droloxifene, lasofoxifene or fosomax), and immunosuppressantagents (e.g., FK-506 and rapamycin).

Biological Activity

The activity of the compounds of the invention for the variousTGF-related disease states as described herein can be determinedaccording to one or more of the following assays. According to theinvention, a compound of the invention exhibits an in vitro IC₅₀ valueof less than about 10 μM. For example, the compound of Example 12exhibits a TβRI IC₅₀ value of about 44.5 nM.

The compounds of the present invention also possess differentialactivity (i.e. are selective for) for TβRI over TβRII and TβRIII.Selectivity is measured in standard assays as a IC₅₀ ratio of inhibitionin each assay.

TGF-β Type II Receptor (TβRII) Kinase Assay Protocol

Phosphorylation of myelin basic protein (MBP) by the TβRII kinase wasmeasured as follows: 80 microliters of MBP (Upstate Biotechnology#13-104) diluted in kinase reaction buffer (KRB) containing 50 mM MOPS,5 mM MgCl₂, pH 7.2 to yield a final concentration of 3 micromolar MBPwas added to each well of a Millipore 96-well multiscreen-DP 0.65 micronfiltration plate (#MADPNOB50). 20 microliters of inhibitor diluted inKRB was added to appropriate wells to yield the desired finalconcentration (10-0.03 micromolar). 10 microliters of a mixture of ATP(Sigma #A-5394) and ³³P-ATP (Perkin Elmer #NEG/602H) diluted in KRB wasadded to yield a final concentration of 0.25 micromolar ATP and 0.02microcuries of ³³P-ATP per well. 10 microliters of a GST-TβRII fusionprotein (glutathione S-transferase at the N-terminal end of thecytoplasmic domain of TβRII—amino acids 193-567 with A to V change at438) diluted in KRB was added to each well to yield a finalconcentration of 27 nanomolar GST-TβRII. Plates were mixed and incubatedfor 90 minutes at room temperature. After the reaction incubation, 100microliters of cold 20% trichloroacetic acid (Aldrich #25,139-9) wasadded per well and plates were mixed and incubated for 60 minutes at 4°C. Liquid was then removed from the wells using a Millipore vacuummanifold. Plates were washed once with 200 microliters per well of cold10% trichloroacetic acid followed by two washes with 100 microliters perwell of cold 10% trichloroacetic acid. Plates were allowed to dryovernight at room temperature. 20 microliters of Wallac OptiPhaseSuperMix scintillation cocktail was added to each well. Plates weresealed and counted using a Wallac 1450 Microbeta liquid scintillationcounter. The potency of inhibitors was determined by their ability toreduce TβRII-mediated phosphorylation of the MBP substrate.

ALK-5 (TβRI) Kinase Assay Protocol

The kinase assays were performed with 65 nM GST-ALK5 and 84 nM GST-Smad3in 50 mM HEPES, 5 mM MgCl₂, 1 mM CaCl₂, 1 mM dithiothreitol, and 3_MATP. Reactions were incubated with 0.5_Ci of [33 P]_ATP for 3 h at 30°C. Phosphorylated protein was captured on P-81 paper (Whatman,Maidstone, England), washed with 0.5% phosphoric acid, and counted byliquid scintillation. Alternatively, Smad3 or Smad1 protein was alsocoated onto FlashPlate Sterile Basic Microplates (PerkinElmer LifeSciences, Boston, Mass.). Kinase assays were then performed inFlash-Plates with same assay conditions using either the kinase domainof ALK5 with Smad3 as substrate or the kinase domain of ALK6 (BMPreceptor) with Smad1 as substrate. Plates were washed three times withphosphate buffer and counted by TopCount (Packard Bio-science, Meriden,Conn.). (Laping, N.J. et al. Molecular Pharmacology 62:58-64 (2002)).

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (d) and are referenced to the deuteriumlock signal from the sample solvent (deuteriochloroform unless otherwisespecified). Mass Spectral data were obtained using a Micromass ZMD APCIMass Spectrometer equipped with a Gilson gradient high performanceliquid chromatograph. The following solvents and gradients were used forthe analysis. Solvent A; 98% water/2% acetonirile/0.01% formic acid andsolvent B; acetonitrile containing 0.005% formic acid. Typically, agradient was run over a period of about 4 minutes starting at 95%solvent A and ending with 100% solvent B. The mass spectrum of the majoreluting component was then obtained in positive or negative ion modescanning a molecular weight range from 165 AMU to 1100 AMU. Specificrotations were measured at room temperature using the sodium D line (589nm). Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide.Chromatography refers to column chromatography performed using 32-63 mmsilica gel and executed under nitrogen pressure (flash chromatography)conditions. Room or ambient temperature refers to 20-25° C. Allnon-aqueous reactions were run under a nitrogen atmosphere forconvenience and to maximize yields. Concentration at reduced pressuremeans that a rotary evaporator was used.

One of ordinary skill in the art will appreciate that in some casesprotecting groups may be required during preparation. After the targetmolecule is made, the protecting group can be removed by methods wellknown to those of ordinary skill in the art, such as described in Greeneand Wuts, “Protective Groups in Organic Synthesis” (2^(nd) Ed, JohnWiley & Sons 1991).

Analytical high performance liquid chromatography on reverse phase withmass spectrometry detection (LSMS) was done using Polaris 2×20 mm C18column. Gradient elution was applied with increase of concentration ofacetonitrile in 0.01% aqueous formic acid from 5% to 100% during 3.75min period. Mass spectrometer Micromass ZMD was used for molecular ionidentification.

EXAMPLE 1 Preparation of1-Methyl-6-[5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1H-benzotriazole

Step A: Preparation of 3-Methyl-3H-benzotriazole-5-carboxylic acidmethoxy-methyl-amide

3-Methyl-3H-benzotriazole-5-carboxylic acid (1.67 g, 5.6 mmol) wassuspended in 25 ml N,N-dimethylformamide. 1,1′-carbonyldiimidazole (1.0g, 6.2 mmol) was added and the reaction stirred at room temperature for90 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (593 mg, 6.2mmol) was added and the reaction stirred at room temperature overnight.The solvent was removed by rotary evaporation. The residue was dissolvedin saturated aqueous ammonium chloride solution and extracted threetimes with chloroform. The combined organics were dried over sodiumsulfate, filtered and concentrated to dryness. Crude material waspurified on Biotage Flash 40S silica gel column usingchloroform/methanol gradient system (100:0 to 97:3, respectively) aseluent to afford 3-methyl-3H-benzotriazole-5-carboxylic acidmethoxy-methyl-amide (1.0 g, 82%).

Step B: Preparation of1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone

A solution of 2,6-dimethylpyridine (292 μl, 2.5 mmol) in 10 ml anhydroustetrahydrofuran was cooled to −30° C. A 2.5M solution of n-butyllithiumin hexanes (1.0 ml, 2.5 mmol) was slowly added dropwise. Once theaddition was complete, the reaction was stirred at

−30° C. for 1 hour. In a separate flask, a solution of3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (500mg, 2.27 mmol) in 3 ml anhydrous tetrahydrofuran was cooled to −30° C.The cold anion solution was slowly added dropwise to the cold amidesolution. Once the addition was complete, the reaction was allowed toslowly warm to room temperature over several hours and stirredovernight. The reaction was quenched with water and the solvent removedby rotary evaporation. The residue was dissolved in saturated aqueousammonium chloride and extracted three times with chloroform. Thecombined organics were washed once with water and then once with brine.The combined organics were dried over sodium sulfate, filtered andconcentrated to dryness. Crude material was purified on Biotage Flash40S silica gel column using hexanes/ethyl acetate gradient system (80:20to 40:60, respectively) as eluent to afford1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone(320 mg, 53%).

Step C: Preparation of1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione

A solution of1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone(280 mg, 1.05 mmol) in 16 ml dimethyl sulfoxide was heated to 60° C. 48%hydrobromic acid solution in water (7.4 ml, 65.1 mmol) was slowly addedover several minutes. Once the addition was complete, the reaction wasstirred at 60° C. for 3 hours. The reaction was cooled to roomtemperature and poured into 75 ml water. The pH was adjusted to 8 withthe addition of saturated sodium hydrogen carbonate solution. Theaqueous layer was then extracted three times with ethyl acetate. Thecombined organics were dried over sodium sulfate, filtered andconcentrated to afford1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione(146 mg, 50%).

Step D. Preparation of1-Methyl-6-[5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1H-benzotriazole

In a threaded glass pressure tube was combined1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione(35 mg, 0.125 mmol), 37% formaldehyde solution in water (14 μl, 0.188mmol), ammonium acetate (97 mg, 1.25 mmol), 2 ml methyl t-butyl etherand 2 ml methanol. The tube was sealed and the reaction heated at 65° C.for two days. The reaction was concentrated to dryness. Crude materialwas purified on Biotage Flash 12S silica gel column usingchloroform/methanol gradient system (99:1 to 90:10, respectively) aseluent to afford1-Methyl-6-[5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1H-benzotriazole(8 mg, 22%). HPLC t_(R)=3.30 min, LC-MS=291 (M+1).

EXAMPLE 26-[5-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=2.92 min, LC-MS=277 (M+1).

EXAMPLE 32-Methyl-5-[5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=4.00 min, LC-MS=291 (M+1).

EXAMPLE 42-Methyl-5-[2-methyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.84 min, LC-MS=305 (M+1).

EXAMPLE 56-[2-tert-Butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol4-yl]-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.27 min, LC-MS=319 (M+1).

EXAMPLE 61-Methyl-6-[5-(6-methyl-pyridin-2-yl)-2-trifluoromethyl-1H-imidazol-4-yl]-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=4.45 min, LC-MS=359 (M+1).

EXAMPLE 72-[2-Methyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-[1,5]naphthyridine

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.12 min, LC-MS=302 (M+1).

EXAMPLE 82-[2-Methyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol4-yl]-[1,5]naphthyridine

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.12 min, LC-MS=302 (M+1).

EXAMPLE 96-[2-Methyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=2.89 min, LC-MS=291 (M+1).

EXAMPLE 101-Methyl-6-[2-methyl-5-(6-methyl-pyridin-2-yl-1H-imidazol-4-yl]-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.25 min, LC-MS=305 (M+1).

EXAMPLE 111-Methyl-6-(2-methyl-5-pyridin-2-yl-1H-imidazol-4-yl)-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=2.93 min, LC-MS=291 (M+1).

EXAMPLE 121-Methyl-6-[5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=2.92 min, LC-MS=277 (M+1).

EXAMPLE 132-[5-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-[1,5]naphthyridine

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.16 min, LC-MS=288 (M+1).

EXAMPLE 146-[2-Methyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-3-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.9 min, LC-MS=359 (M+1).

EXAMPLE 156-[2-Methyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-3-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.83 min, LC-MS=345 (M+1).

EXAMPLE 164-[4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-phenol

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=4.36 min, LC-MS=383 (M+1).

EXAMPLE 174-[4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-benzonitrile

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=5.29 min, LC-MS=392 (M+1).

EXAMPLE 185-[2-(2-Benzo[1,3]dioxol-5-yl-1-methyl-ethyl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=5.2 min, LC-MS=453 (M+1).

EXAMPLE 192-Methyl-5-[5-(6-methyl-pyridin-2-yl)-2-(2-methylsulfanyl-ethyl)-1H-imidazol-4-yl]-2H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=4.12 min, LC-MS=365 (M+1).

EXAMPLE 202-Methyl-5-[5-(6-methyl-pyridin-2-yl)-2-thiazol-2-yl-1H-imidazol-4-yl]-2H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=4.75 min, LC-MS=374 (M+1).

EXAMPLE 216-[2-Cyclopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-1-methyl-1H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.62 min, LC-MS=331 (M+1).

EXAMPLE 225-[2-Cyclopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.82 min, LC-MS=331 (M+1).

EXAMPLE 236-[2-Cyclopropyl-5-(6-methyl-pyridin-2-yl-1H-imidazol-4-yl]-quinoxaline

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.73 min, LC-MS=328 (M+1).

EXAMPLE 24 Preparation of[4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-methanol

Step A:5-[2-Dimethoxymethyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole

5-[2-Dimethoxymethyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazolewas prepared according to procedures analogous to those described inExample 1. LC-MS=365 (M+1).

Step B:4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde

5-[2-Dimethoxymethyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole(700 mg, 1.92 mmol) was dissolved in 40 ml anhydrous tetrahydrofuran. 6Mhydrochloric acid solution in water (3.2 ml, 19.2 mmol) was added. Thereaction was refluxed for 3 hours and then cooled to room temperature.Saturated aqueous sodium hydrogen carbonate solution was added untilapproximately pH 8. The organic solvent was removed by rotaryevaporation. The residue was dissolved in water and then extracted threetimes with chloroform. The combined organic extracts were dried oversodium sulfate, filtered, and concentrated to afford4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde(600 mg, 98% yield) as a brown solid.

Step C.[4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-methanol

4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde(20 mg, 0.063 mmol) was dissolved in 2 ml anhydrous methanol. Sodiumborohydride (3 mg, 0.069 mmol) was added and the reaction stirred atroom temperature for 1 hour. The reaction was quenched with water andsolvent was removed by rotary evaporation. The residue was purified onBiotage Flash 12S silica gel column using chloroform/methanol gradientsystem (97:3 to 95:5, respectively) as eluent to afford[4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-methanol(13 mg, 64% yield) as a white solid. HPLC t_(R)=3.18 min, LC-MS=321(M+1).

EXAMPLE 25 Preparation ofDimethyl-[4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-ylmethyl]-amine

2M solution of dimethylamine in tetrahydrofuran (189 μl, 0.378 mmol) wasdissolved in 2 ml anhydrous methanol. Glacial acetic acid was addeduntil approximately pH 4.4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde(20 mg, 0.063 mmol) was added and the reaction stirred at roomtemperature for 3 hours. Sodium cyanoborohydride (6 mg, 0.095 mmol) wasadded and the reaction stirred at room temperature overnight. 1Msolution of sodium hydroxide in water was added until the reaction pHwas 8 and the organic solvent was then removed by rotary evaporation.The residue was dissolved in water and extracted three times withchloroform. The combined organic extracts were dried over sodiumsulfate, filtered, and concentrated to dryness. The residue was purifiedon Biotage Flash 12S silica gel column using chloroform/methanolgradient system (95:5 to 80:20, respectively) as eluent to afforddimethyl-[4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-ylmethyl]-amine(6 mg, 28% yield). HPLC t_(R)=3.29 min, LC-MS=348 (M+1).

EXAMPLE 26 Preparation of4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylicacid amide

Suspension of ammonium chloride (12 mg, 0.21 mmol) in 2 ml dry benzenewas cooled to 0° C. 2M solution of trimethylaluminum in toluene (105 μl,0.21 mmol) was slowly added and the reaction warmed to room temperatureand stirred for 2 hours. This suspension was added to separatesuspension of4-(2-ethyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylicacid methyl ester (25 mg, 0.07 mmol)(prepared according to proceduresanalogous to example 1) in 1 ml dry benzene and the reaction heated at50° C. overnight. The reaction was quenched by the addition of excess 1M aqueous solution of hydrochloric acid. The reaction was extractedthree times with chloroform. Mass spectrometry analysis of organicextracts show no presence of desired product. The remaining aqueouslayer was concentrated to dryness. The aqueous extract reside waspurified on Biotage Flash 12S silica gel column usingchloroform/methanol gradient system (99:1 to 80:20, respectively) aseluent to afford4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylicacid amide (4 mg, 16% yield). HPLC t_(R)=3.70 min, LC-MS=344 (M+1).

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety.

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed are only illustrative of theinvention. Accordingly, the invention is limited only by the followingclaims.

1. A compound of formula (Ia):

or a pharmaceutically acceptable salt, prodrug, or tautomer wherein: R¹is a saturated, unsaturated, or aromatic bi- or polycyclic ringcontaining at least one heteroatom selected from the group consisting ofN, O and S, wherein R¹ can optionally be further independentlysubstituted with at least one moiety independently selected from thegroup consisting of: carbonyl, halo, halo(C₁-C₆)alkyl,perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy, oxo, mercapto, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy,(C₅-C₁₀)alkyl or (C₅-C₁₀)heteroaryl, (C₅-C₁₀)aryloxy or(C₅-C₁₀)heteroaryloxy, (C₅-C₁₀)ar(C₁-C₆)alkyl or(C₅-C₁₀)heteroar(C₁-C₆)alkyl, (C₅-C₁₀)ar(C₁-C₆)alkoxy or(C₅-C₁₀)heteroar(C₁-C₆)alkoxy, HO—(C═O)—, ester, amido, ether, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl,(C₁-C₆)alkyl- and di(C₁-C₆)alkylamino, cyano, nitro, carbamoyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylaminocarbonyl,di(C₁-C₆)alkylaminocarbonyl, (C₅-C₁₀)arylcarbonyl,(C₅-C₁₀)aryloxycarbonyl, (C₁-C₆)alkylsulfonyl, and (C₅-C₁₀)arylsulfonyl;each R³ is independently selected from the group consisting of:hydrogen, halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C_(1-C) ₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₅-C₁₀)heteroaryl-O—,(C₅-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, -C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, O₂N—, NC—, amino,Ph(CH₂)₁₋₆HN—, (C₁-C₆)alkyl HN—, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, amino(C═O)—, aminoO₂S—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, (C₅C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—and(C₁-C₆)alkyl-(C═O)—O—; where alkyl, alkenyl, alkynyl, phenyl,heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R³ isoptionally substituted by at least one substituent independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂N—,Ph(CH₂)₆HN—, and (C₁-C₆)alkylHN—; s is an integer from one to four; R⁴is independently selected from the group consisting of: hydrogen, halo,halo(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,phenyl, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₅-C₁₀)heteroaryl-O—, (C₅-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, C₁-C₆)alkyl-S—(C₁-C₆)alkyl-, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, O₂N—, NC—, amino, aminoalkyl, Ph(CH₂)₁₋₆HN—,(C₁-C₆)alkylHN—, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino,(C₁-C₆)alkyl-SO₂—NH—, amino(C═O)—, aminoO₂S—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—((C₁-C₆)alkyl)-N—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, ((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-NH —(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, and(C₁-C₆)alkyl-(C═O)—O—; where, alkenyl, alkynyl, phenyl, heteroaryl,heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R⁴ is optionallysubstituted by at least one substituent independently selected from thegroup consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo,H₂N—, NC—, HO—, Ph (CH₂)₁₋₆HN—, (C₁-C₆)alkylHN—, (C₅-C₁₀)heteroaryl and(C₅-C₁₀)heterocyclyl; R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,(C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,(C₁-C₆)alkyl-(SO₂)—, (C₁-C₆)alkyl-(SO₂)—(C₁-C₆)alkyl, phenyl-(SO₂)—,H₂N—(SO₂)—, (C₁-C₆)alkyl-NH—(SO₂)—, (C₁-C₆)alkyl-(SO₂)—NH—(C₁-C₆)alkyl,(C₁-C₆)alkyl-NH—(SO₂)—(C₁-C₆)alkyl, ((-C₁-C₆)alkyl)₂N—(SO₂)—,phenyl-NH—(SO₂)—, (phenyl)₂N—(SO₂)—, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-(C═O)—(C₁-C₆)alkyl, phenyl-(C═O)—,(C₅-C₁₀)heteroary1-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—(C₃-C₁₀)cycloalkyl,C₁-C₆)alkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—NH—(C₁-C₆)alkyl,phenyl-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—(C₃-C₁₀)cycloalkyl,(C₃C₁₀)cycloalkyl-(C═O)—NH—(C₃-C₁₀)cycloalkyl, ((C₁-C₆)alkyl)₂N—(C═O)—,(phenyl)₂N—(C═O)—, phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heteroaryl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heterocyclic-[((C₁-C₆)alkyl)-N]—(C═O)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)-N]—(C═O)—; where alkyl, alkenyl,alkynyl, phenyl, benzyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy,phenoxy, amino of R⁶ is optionally substituted with at least one moietyindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₅-C₁₀)heterocyclic, (C₅C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, NC—, (C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₅-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₅-C₁₀)heterocyclic-O—, (C₅-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₅-C₁₀)heterocyclic-(C═O)—O—, (C₅-C₁₀)heteroaryl-(C═O)—O—, O₂N—, amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₅-C₁₀)heterocyclic-(C═O)—NH—, (C₅-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-(C═O)—[(C₁-C₆)alkyl-N],(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—,(C₅-(C₁₀)heterocyclic-SO₂NH—and (C₅-C₁₀)heteroaryl-SO₂NH—; wherein thephenyl or heteroaryl moiety of a R⁶ substituent is optionally furthersubstituted with at least one radical independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,perfluoro(C₁-C₆)alkyl and perfluoro(C₁-C₆)alkoxy, with the proviso thatwhen R⁴ is a substituted phenyl group, then (a) R¹ is not a naphthyl,anthracenyl or phenyl and (b) if R¹ is a phenyl fused with an aromaticor non-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to three heteroatoms independently selected fromN, O and S, then the fused cyclic ring of said R¹ moiety is substituted;and with the proviso that when R⁴ is hydrogen, then (a) R¹ is not anaphthyl or phenyl and (b) if R¹ is a phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members wherein said cyclic ringoptionally contains up to three heteroatoms independently selected fromN, O and S, then the fused cyclic ring of said R¹ moiety is substituted;and with the proviso that when it is not hydrogen or substituted phenyl,then (a) R¹ is not a naphthyl, anthracenyl or phenyl and (b) if R¹ is aphenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of5-7 members wherein said cyclic ring optionally contains up to threeheteroatoms independently selected from N, O and S, and is optionallysubstituted by oxo, then the fused cyclic ring of said R¹ moietycontains at least one substituted heteroatom.
 2. A compound of claim 1,wherein R¹ is


3. A compound of claim 1, wherein R¹ is


4. A compound of claim 1, wherein R¹ is


5. A compound of claim 1, wherein R¹ is


6. A compound of claim 1, wherein R¹ is


7. A compound of claim 1, wherein s is one to two; R³ is hydrogen or(C₁-C₆)alkyl; R⁴ is hydrogen, (C₁-C₆)alkyl.
 8. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.